Remarkable improvements in the outcomes of children with leukemia have been realized in the last few decades, so that what was death sentence 30 years ago is now curable in 70% of cases. However, the prognosis remains poor for children with acute myelogenous leukemia (AML) and for infants with acute lymphoblastic leukemia (ALL), whose cure rates are 40% and 20%, respectively. Novel treatments are needed. There is convincing evidence that activation of the tyrosine kinase FLT3 contributes to the pathogenesis of these diseases, and small molecule inhibitors of FLT3 are selectively cytotoxic to primary blasts from these patients. Our hypothesis is that FLT3 inhibitors, if rationally incorporated into current treatment regimens, will improve the outcome of children with AML and infants with ALL. The scientific objective of this proposal is to accelerate the clinical development of FLT3 inhibitors as a component of therapy for these patients. We propose two specific aims: (1) to use in vitro and in vivo preclinical experiments with primary patient samples to determine the optimal strategy for incorporating FLT3 inhibitors into existing treatment regimens of children with leukemia, and (2) to conduct clinical trials of a FLT3 inhibitor in pediatric leukemia, and utilize correlative and surrogate assays of the biologic effects of FLT3 inhibition on samples from these patients to accelerate and optimize drug development. The long term career goal of the principal investigator, Dr, Patrick Brown, is to independently conduct clinical and translational research that results in improved outcome for children with leukemia. Immediate career goals are to (1) develop progressive expertise in laboratory-based translational research of targeted therapeutics for leukemia, and (2) develop expertise in the design and conduct of clinical trials investigating the use of these agents to treat children with leukemia. A mentoring committee composed of seasoned investigators with complementary research skills will guide the principal investigator through a series of phased research endeavors in a rich academic institutional environment with a strong commitment to the investigator's career. The proposed training includes mentored clinical trial leadership and translational research;didactic instruction in the science of clinical investigation, the biology of leukemia and the responsible conduct of research;and participation in the clinical care of children with cancer.